the physiology of hemostasis ira a. shulman, md professor and vice chair of pathology keck school of...
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The Physiology of HemostasisIra A. Shulman, MD Professor and Vice Chair of PathologyKeck School of Medicine of USCMedical Director of Transfusion ServiceUSC Norris Cancer HospitalLos Angeles, California
2
Activity Goals
In this presentation, you will learn about:
• Essential scientific components of hemostasis
• The causes of and approximate frequencies of excessive surgical bleeding
• How surgical complications, regardless of surgery type, can be attributed to bleeding and clotting
• The importance of determining which patients are at greatest risk for surgical coagulopathy
• How achieving optimal hemostasis can be viewed as a “balancing act”
3
Prevalence of Uncontrolled Bleeding
Surgical Discipline Uncontrolled Bleeding Rate
Cardiovascular 5%-7% post-op1
General 1.9% laparoscopic cholecystectomy2
Obstetric 3.9% (vaginal); 6.4% (cesarean)3,4
Orthopedic 2%-6.3% hip/knee arthroplasty5-7
Urologic 4%-8% TURP8; 3.3%-9.9% URL9
Trauma 30%-40%10,11
1. Despotis GJ, et al. Anesth Analg. 1996;82:13-21. 2. Erol DD, et al. Internet J Anesth. 2005;9:2. 3. Combs CA, et al. Obstet Gynecol. 1991;77:69-76. 4. Combs CA, et al. Obstet Gynecol. 1991;77:77-82. 5. Hull R, et al. N Engl J Med. 1993;329:1370-1376. 6. Leclerc JR, et al. Ann Intern Med. 1996;124:619-626. 7. Strebel N, et al. Arch Intern Med. 2002;162:1451-1455. 8. Daniels PR. Nat Clin Pract Urol. 2005;2:343-350. 9.Rosevear HM, et al. J Urol. 2006;176:1458-1462. 10. Holcomb JB. Crit Care. 2004;8(suppl 2):S57-S60. 11. Sauaia A, et al. J Trauma. 1995;38:185-193.
TURP=transurethral prostatic resection.
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Definition of Hemostasis
Hemostasis: “The arrest of bleeding”Stedman’s Medical Dictionary
Hemostasis: “Life in the balance”
Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64.
• Trauma• Major surgery• Hemophilia
• Stroke• Myocardial infarction (MI)• Thrombosis
Bleedingto Death
Clottingto Death
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Definition of Significant Bleeding
• >2 L blood loss in an adult within first 24 post-op hours1
Volume of acute blood loss/patient weight >30 mL/kg
Volume of acute blood loss >40%-50% total blood volume
• Surgical or vascular component: corrected by surgical
intervention or embolization2
• Coagulopathic component: more difficult to control due
to several interrelated mechanisms2
Consumption of coagulation factors and platelets
Dilution of coagulation factors
Metabolic disorders (eg, hypothermia, acidosis)
1. Despotis GJ, et al. Ann Thorac Surg. 2000;70(suppl 2):S20-S32. 2. Vincent J-L, et al. Crit Care. 2006;10:1-12.
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Reasons for Uncontrolled Bleeding
Patient-related• Advanced age• Small body size• Gender• Pre-op anemia
(low RBC volume) • Antiplatelet or antithrombotic
drugs• Hypothermia• Acidosis• Systemic inflammatory
response syndrome (SIRS)• Comorbidities:
Congestive heart failure Hypertension Chronic obstructive
pulmonary disease Peripheral vascular disease Diabetes mellitus Renal failure
Procedure-related• Prolonged operation• CABG• Emergency/trauma• Surgical-site bleeding• Surgical skill
Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86.
RBC=red blood cell; CABG=coronary artery bypass graft.
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SurgeryPost-op Recovery
Thrombosis
Clotting
Bleeding
Hemorrhage
Can We Predict Who Will Bleed?
Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64.
• Who is likely to bleed or clot too much?• How do we optimize the patient’s physiology?• Which topical agents are effective?• Which biologic agents are effective?
There Is a Difference Between Who Is at Risk and Who Will Bleed
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Patients at Risk for Surgical Bleeding
Certain patients are at higher risk for surgical bleeding, including:
• Patients taking Long-acting anticoagulant therapy Clopidogrel
• Patients undergoing Repeat surgical procedures Oncologic surgery Aortic surgery Cardiac surgery Neurologic procedures or neurosurgery Radical prostatectomy
• Dialysis patients
• Trauma patients
Ferraris VA, et al. . Ann Thorac Surg. 2007;83:S27–S86; Disorders of Hemostasis. In: Harrison’s Internal Medicine. New York, NY: Mc-Graw Hill; 2007. Available at: http://www.accessmedicine.com/resourceToc.aspx?resourceID=4. Tanaka KA, et al. Anesthesiology. 2003;98:1513-1515.
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Conditions Associated With Coagulopathy
• Hemophilia
• Platelet disorders
• Liver disease
• Uremia
• Disseminated intravascular coagulation (DIC)
• Dilutional coagulopathy
• Anticoagulant treatment
• Acidosis
• Hypothermia
• Extracorporeal circuits
Ferraris VA, et al. . Ann Thorac Surg. 2007;83:S27–S86.Disorders of Hemostasis. In: Harrison’s Internal Medicine. New York, NY: Mc-Graw Hill; 2007. Available at: http://www. accessmedicine.com/resourceToc.aspx?resourceID=4.
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Thienopyridines Such as Clopidogrel and Postoperative Bleeding
• Evidence is more compelling than for aspirin1
11 studies of clopidogrel and CABG
All studies show increased bleeding when
clopidogrel given within 5 days of CABG — some
with increased mortality
• ACC/AHA and STS/SCA guidelines recommend
stopping clopidogrel for 5 days before surgery (if
possible)1,2
1. Ferraris VA, et al. Ann Thorac Surg. 2005;79:1454-1461. 2. Braunwald E, et al. J Am Coll Cardiol. 2002;40:1366-1374.
CABG=coronary artery bypass graft.
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Traditional Model of Hemostasis
Intrinsic Pathway Extrinsic Pathway
factor XIIHMKPK
factor XI factor XIa
factor IXfactor IXa
factor VIIIaPL, Ca+2
factor Xfactor Xafactor VaPL, Ca+2
prothrombin thrombin
fibrinogen fibrin
factor VIIatissue factor
PL, Ca+2
factor X
Adapted from Hoffman M, et al. Thromb Haemost. 2001;85:958-965.
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Vascular Spasm
Currie D. Available at: http://faculty.etsu.edu/currie/hemostasis.htm. Accessed May 6, 2008.
Blood vessel
Vascular spasm
Region of trauma
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Platelet Plug Formation—Primary Hemostasis
Reprinted with permission from Rinder C. In: Spiess BD, et al, eds. Perioperative Transfusion Medicine. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:chap 8.©2005 Lippincott Williams & Wilkins http://lww.com
Platelet adhesion to subendothelial vWF
vWF=von Willebrand factor; GP=glycoprotein.
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Platelet Plug Formation—Primary Hemostasis
Reprinted with permission from Rinder C. In: Spiess BD, et al, eds. Perioperative Transfusion Medicine. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:chap 8.©2005 Lippincott Williams & Wilkins http://lww.com
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Vascular Endothelium Serves As a “Front Line”Defense Against Pathologic Thrombosis
This figure was published in Semin Hematol, Vol 41(suppl 1), Lawson JH, et al, “Challenges for Providing Effective Hemostasis,” pp 55-64, ©Elsevier 2004.
16Hoffman M, et al. Blood Coag Fibrinol. 1998;9(suppl 1):S61-S65.
TF-Bearing Cell
Activated Platelet
Platelet
TF
VIIIa Va
VIIIaVa
Va
VIIa
TF VIIa Xa
X II
IIa
IXV Va
II
VIII/vWF
VIIIa
II
IXa
XIX
X
IXa
IXaVIIa
Xa
IIa
IIa
Xa
Evolving Model of Hemostasis
TF=tissue factor; vWF=von Willebrand factor.
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Fibrinolysis
tPA=tissue plasminogen activator; PAI-1=plasminogen activator inhibitor 1; AP=anti-plasmin;PAP=plasmin-anti-plasmin complexes.
Reprinted with permission from Chandler WL. In: Spiess BD, et al, eds. Perioperative Transfusion Medicine. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:chap 7.©2005 Lippincott Williams & Wilkins http://lww.com
Endothelium Endothelium
tPAPAI-1
tPA-PAI-1
PAPAP
D-dimerPlasmintPA + Plasminogen
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Putting It All Together
Reprinted with permission from Chandler WL. In: Spiess BD, et al, eds. Perioperative Transfusion Medicine. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:chap 7.©2005 Lippincott Williams & Wilkins http://lww.com
Wound: collagen and tissue factor exposure Fibrin formation, clot stabilization
Platelet binding and coagulation initiation Platelet contraction, wound healing, fibrin removal
Platelet aggregation Wound healed
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Normal Hemostasis Is a Balance
Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64.
• Trauma• Major surgery• Hemophilia
• Stroke• MI• Thrombosis
Bleedingto Death
Clottingto Death
• Blood coagulation• Anticoagulation• Fibrinolysis• Antifibrinolysis• Vascular tone and blood flow• Endothelial cells and platelets
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“Keeping on Center”: Moving Toward Normal Hemostasis
NormalHemostasis
ProcoagulantActivity
AnticoagulantActivity
FibrinolyticActivity
AntifibrinolyticActivity
Bleeding
Clotting
Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.
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“Keeping on Center” (cont)
Topical HemostaticsPurified Factors, FFP, Cryo, PLTs
Aminocaproic acidTranexamic acid
Heparin, WarfarinLMWH, Argatroban
t-PA, SK, UPA
NormalHemostasis
Bleeding
Clotting
FFP=fresh frozen plasma; Cryo=cryoprecipitate; PLTs=platelets; SK=streptokinase; UPA=urinary-type plasminogen activator; LMWH=low-molecular-weight heparin.
ProcoagulantActivity
AnticoagulantActivity
FibrinolyticActivity
AntifibrinolyticActivity
Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.
22Adapted from Reed RL, et al. Circ Shock. 1990;32:141-152.
**
**
**
**
**P<.0001 vs clotting time at 37oC.
Temperature (oC) Temperature (oC)
**
**
**
*
*
**P<.0001 vs clotting time at 37oC.
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22
24
26
28
30
32
23 25 27 29 31 33 35 37
Th
rom
bin
Tim
e (s
ec)
Temperature (oC)
**P<.0001 vs clotting time at 37oC.*F<.005 vs clotting time at 37oC.
**
**
*
Effect of Temperature on Test Results of aPTT, TT, and PT
aPTT=activated partial thromboplastin time; PT=prothrombin time; TT=thrombin time.
25
30
35
40
45
50
55
60
65
70
23 25 27 29 31 33 35 37 39
aPT
T (
sec)
10
12
14
16
18
20
22
24
26
23 25 27 29 31 33 35 37 39
Pro
thro
mb
in T
ime
(sec
)*
*
29 volunteers had 2 U RBC removed by apheresis (re-infusion of PRP)
11 received back autologous RBC
18 did not receive back their RBC
Valeri et al. Transfusion 2001;41:977-83.
Effect of 2-unit RBC apheresis or plateletspheresis on bleeding time
0
1
2
3
4
5
6
7
8
9
RBCs Platelets
BT
at
35°
C
ApheresisHct: 41 35 (15%) 40 40Platelet count: 220 200 (9%) 238 163 (32%)
Apheresis Returnof RBCs
Apheresis Returnof RBCs
Does Anemia Induce Reversible Platelet Dysfunction?
Beforeapheresis
0.50
1.00
1.50
2.00
1 Hour TX1 TX2 1 DAY 2 DAY 3 DAY 7 DAY
Te
mp
late
BT
(ra
tio
aft
er:b
efo
re a
ph
ere
sis
)
0.70
0.80
0.90
1.00
1.10
Beforeapheresis
1 Hour TX1 TX2 1 DAY 2 DAY 3 DAY 7 DAY
Per
iph
era
l V
en
ou
s H
ct
(rat
io a
fte
r:b
efo
re a
ph
ere
sis
)
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• During room-temperature storage in the blood bank, platelets express a number of glycoprotein ligands, making them prothrombotic1-3
• Platelets excrete granules containing cell signaling compounds that are capable of triggering reactions in WBCs, endothelial cells, and other native platelets3,4
• This complex activation biology is recognized as part of the platelet storage lesion4
• In certain circumstances, platelet transfusions might increase risk of stroke or death5
1. Spiess BD. Transfusion. 2007;47:354–356; 2. Seghatchian MJ, et al. Transfus Sci. 1997;18:103-107; 3. Van der Planken MG, et al. Ann Hematol. 1999;78:1-7; 4. Seghatchian J, et al. Transfus Med Rev. 1997;11:130-144; 5. Spiess BD, et al. Transfusion. 2004;44:1143-1148.
The Platelet “Storage Lesion” and the Potential Prothrombotic Effect of Platelets
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Thrombosis
Clotting
Bleeding
Hemorrhage
Physiology and Good Surgery
Topical Hemostatic Agents
Systemic Biologic Therapies
Achieving Optimal Operative Hemostasis
Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.
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Hemostasis: Final Thoughts
• Many surgical complications, regardless of surgery type, can be attributed to bleeding and clotting
• It is important to determine which patients are at greatest risk for surgical coagulopathy
• Achieving optimal hemostasis involves a balancing act, whereby patients must be kept from bleeding or clotting to death through transfusional and nontransfusional therapies
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